Methods of preventing and treating gastrointestinal dysfunction

ABSTRACT

Methods of preventing and treating gastrointestinal dysfunction, particularly postoperative ileus and post-partum ileus, in a patient undergoing surgery or other biological stress by administering 4-aryl-piperidine derivatives are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Application No. 60/526,851 filedDec. 4, 2003, the entire disclosure of which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention generally relates to methods of preventing andtreating gastrointestinal (GI) dysfunction. More specifically, thepresent invention relates to methods of preventing and treatinggastrointestinal dysfunction, particularly postoperative ileus andpost-partum ileus, in a patient undergoing surgery or other biologicalstress, by administering 4-aryl-piperidine derivatives.

BACKGROUND OF THE INVENTION

It is well known that opioid drugs target three types of endogenousopioid receptors (i.e., μ, δ, κ receptors) in biological systems. Manyopiates, such as morphine, are mu opioid agonists that are often used asanalgesics for the treatment of severe pain due to their activation ofmu opioid receptors in the brain and central nervous system (CNS).Opioid receptors are, however, not limited to the CNS, and may be foundin other tissues throughout the body. A number of side effects of opioiddrugs may be caused by activation of these peripheral receptors. Forexample, administration of mu opioid agonists often results inintestinal dysfunction due to the large number of receptors in the wallof the gut (Wittert, G., Hope, P. and Pyle, D., Biochemical andBiophysical Research Communications, 1996, 218, 877-881; Bagnol, D.,Mansour, A., Akil, A. and Watson, S. J., Neuroscience, 1997, 81,579-591). Specifically, opioids are generally known to cause nausea andvomiting as well as inhibition of normal propulsive gastrointestinalfunction in animals and man (Reisine, T., and Pasternak, G., Goodman &Gilman's The Pharmacological Basis of Therapeutics Ninth Edition, 1996,521-555) resulting in side effects such as, for example, constipation.

Recent evidence has indicated that naturally occurring endogenous opioidcompounds may also affect propulsive activity in the gastrointestinal(GI) tract. Met-enkephalin, which activates mu and delta receptors inboth the brain and gut, is one of several neuropeptides found in the GItract (Koch, T. R., Carney, J. A., Go, V. L., and Szurszewski, J. H.,Digestive Diseases and Sciences, 1991, 36, 712-728). Additionally,receptor knockout techniques have shown that mice lacking mu opioidreceptors may have faster GI transit times than wild-type mice,suggesting that endogenous opioid peptides may tonically inhibit GItransit in normal mice (Schuller, A. G. P., King, M., Sherwood, A. C.,Pintar, J. E., and Pasternak, G. W., Society of Neuroscience Abstracts,1998, 24, 524). Studies have shown that opioid peptides and receptorslocated throughout the GI tract may be involved in normal regulation ofintestinal motility and mucosal transport of fluids in both animals andman (Reisine, T., and Pasternak, G., Goodman & Gilman's ThePharmacological Basis of Therapeutics Ninth Edition, 1996, 521-555).Other studies show that the sympathetic nervous system may be associatedwith endogenous opioids and control of intestinal motility (Bagnol, D.,Herbrecht, F., Jule, Y., Jarry, T., and Cupo, A., Regul. Pept., 1993,47, 259-273). The presence of endogenous opioid compounds associatedwith the GI tract suggests that an abnormal physiological level of thesecompounds may lead to bowel dysfunction.

It is a common problem for patients having undergone surgicalprocedures, especially surgery of the abdomen, to suffer from aparticular bowel dysfunction called post-surgical (or postoperative)ileus. “Ileus,” as used herein, refers to the obstruction of the bowelor gut, especially the colon. See, e.g., Dorland's Illustrated MedicalDictionary, p. 816, 27th ed. (W.B. Saunders Company, Philadelphia 1988).Ileus should be distinguished from constipation, which refers toinfrequent or difficulty in evacuating the feces. See, e.g., Dorland'sIllustrated Medical Dictionary, p. 375, 27th ed. (W.B. Saunders Company,Philadelphia 1988). Deus may be diagnosed by the disruption of normalcoordinated movements of the gut, resulting in failure of the propulsionof intestinal contents. See, e.g., Resnick, J. Am. J. ofGastroenterology, 1992, 751 and Resnick, J. Am. J. of Gastroenterology,1997, 92, 934. In some instances, particularly following surgery,including surgery of the abdomen, the bowel dysfunction may become quitesevere, lasting for more than a week and affecting more than one portionof the GI tract. This condition is often referred to as post-surgical(or postoperative) paralytic ileus and most frequently occurs afterlaparotomy (see Livingston, E. H. and Passaro, E. D. Jr., DigestiveDiseases and Sciences, 1990, 35, 121). Similarly, post-partum ileus is acommon problem for women in the period following childbirth, and isthought to be caused by similar fluctuations in natural opioid levels asa result of birthing stress.

Gastrointestinal dysmotility associated with post-surgical ileus isgenerally most severe in the colon and typically lasts for 3 to 5 days.The administration of opioid analgesics to a patient after surgery mayoften contribute to bowel dysfunction, thereby delaying recovery ofnormal bowel function. Since virtually all patients receive opioidanalgesics, such as morphine or other narcotics for pain relief aftersurgery, particularly major surgery, current post-surgical paintreatment may actually slow recovery of normal bowel function, resultingin a delay in hospital discharge and increasing the cost of medicalcare.

Post-surgical ileus may also occur in the absence of exogenous opioidagonists. It would be of benefit to inhibit the natural activity ofendogenous opioids during and/or after periods of biological stress,such as surgery and childbirth, so that ileus and related forms of boweldysfunction can be prevented or treated. Currently, therapies for ileusinclude functional stimulation of the intestinal tract, stool softeners,laxatives, lubricants, intravenous hydration, and nasogastricdecompression. These prior art methods suffer from drawbacks, forexample, as lacking specificity for post-surgical or post-partum ileus.And these prior art methods offer no means for prevention. If ileuscould be prevented, hospital stays, recovery times, and medical costswould be significantly decreased in addition to the benefit ofminimizing patient discomfort. Thus, drugs which selectively act onopioid receptors in the gut would be ideal candidates for preventingand/or treating post-surgical and post-partum ileus. Of those, drugsthat do not interfere with the effects of opioid analgesics in the CNSwould be of special benefit in that they may be administeredsimultaneously for pain management with limited side effects.

Peripheral opioid antagonists that do not cross the blood-brain barrierinto the CNS are known in the literature and have been tested inrelation to their activity on the GI tract. In U.S. Pat. No. 5,250,542,U.S. Pat. No. 5,434,171, U.S. Pat. No. 5,159,081, and U.S. Pat. No.5,270,328, peripherally selective piperidine-N-alkylcarboxylate opioidantagonists are described as being useful in the treatment of idiopathicconstipation, irritable bowel syndrome and opioid-induced constipation.Also, U.S. Pat. No. 4,176,186 describes quaternary derivatives ofnoroxymorphone (i.e., methylnaltrexone) that are said to prevent orrelieve the intestinal immobility side-effect of narcotic analgesicswithout reducing analgesic effectiveness. U.S. Pat. No. 5,972,954describes the use of methylnaltrexone, enteric-coated methylnaltrexone,or other quaternary derivatives of noroxymorphone for preventing and/ortreating opioid- and/or non-opioid-induced side effects associated withopioid administration.

General opioid antagonists, such as naloxone and naltrexone have alsobeen implicated as being useful in the treatment of GI tractdysmotility. For example, U.S. Pat. No. 4,987,126 and Kreek, M. J.Schaefer, R. A., Hahn, E. F., Fishman, J., Lancet, 1983, 1(8319), 261disclose naloxone and other morphinan-based opioid antagonists (i.e.,naloxone, naltrexone) for the treatment of idiopathic gastrointestinaldysmotility. In addition, naloxone has been shown to effectively treatnon-opioid induced bowel obstruction, implying that the drug may actdirectly on the GI tract or in the brain (Schang, J. C., Devroede, G.,Am. J. Gastroenerol., 1985, 80(6), 407). Furthermore, it has beenimplicated that naloxone may provide therapy for paralytic ileus (Mack,D. J. Fulton, J. D., Br. J. Surg., 1989, 76(10), 1101). However, it iswell known that activity of naloxone and related drugs is not limited toperipheral systems and may interfere with the analgesic effects ofopioid narcotics.

Inasmuch as post-surgical and post-partum ileus, for example, are commonillnesses that add to the cost of health care and as yet have nospecific treatments, there is a need for a specific and effectiveremedy. The majority of currently known opioid antagonist therapies arenot peripherally selective and have the potential for undesirable sideeffects resulting from penetration into the CNS. Given the estimated 21million inpatient surgeries and 26 outpatient surgeries each year, andan estimate of 4.7 million patients experiencing post-surgical ileus,methods involving opioid antagonists that are not only specific forperipheral systems, but specific for the gut, are desirable for treatingpost-surgical and post-partum ileus.

Alvimopan is an orally active, gastrointestinal (GI) restricted μ opioidantagonist being developed to alleviate the GI side effects associatedwith narcotic therapy. This compound differs from previouslycharacterized peripherally selective opioid antagonists by its potencyand degree of peripheral receptor selectivity [Zimmerman et al., J. Med.Chem., 1994, 37, 2262-2265].

In clinical trials, alvimopan had heretofore been administered at leasttwo hours prior to a surgical procedure to block the undesirable effectsof opioid analgesics on the GI tract. Oftentimes, however, there may beinsufficient time to administer the alvimopan at least two hours priorto surgery, especially prior to emergency surgery.

Therefore, it would be desirable to provide methods for preventingand/or treating gastrointestinal dysfunction, particularly postoperativeileus, in a patient undergoing surgery. The methods of the presentinvention are directed toward these, as well as other, important ends.

SUMMARY OF THE INVENTION

The methods of the present invention are directed to treating andpreventing gastrointestinal dysfunction, particularly postoperativeileus and postpartum ileus, in a patient undergoing surgery or otherbiological stress.

In a first aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the freeconcentration in the plasma of said patient of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is sufficient to substantiallysaturate the μ opioid receptors in the gastrointestinal tract of saidpatient;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is sufficient to achieve substantially complete saturation of μopioid receptors in the gastrointestinal tract of said patient;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.

In a second aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes prior to said surgery;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.

In a third aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes after said administration;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.

In a fourth aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the freeconcentration in the plasma of said patient of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is sufficient to substantiallysaturate the vi opioid receptors in the gastrointestinal tract of saidpatient;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is sufficient to achieve substantially complete saturation of μopioid receptors in the gastrointestinal tract of said patient;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is a compound of formula (IA):

wherein:

R¹ is hydrogen or alkyl;

R² is hydrogen, alkyl, or alkenyl;

R³ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁴ is hydrogen, alkyl, or alkenyl;

A is OR⁵ or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substitutedalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, togetherwith the nitrogen atom to which they are attached, R⁶ and R⁷ form aheterocyclic ring;

B is

C(═O)W or NR⁸R⁹;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl,cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R⁸ and R⁹ form a heterocyclic ring;

W is OR¹⁰, NR¹¹R¹², or OE;

R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, togetherwith the nitrogen atom to which they are attached, R¹¹ and R¹² form aheterocyclic ring;

E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴;

R¹³ is alkyl substituted alkylene;

R¹⁴ is alkyl;

D is OR¹⁵ or NR¹⁶R¹⁷;

R¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl;

R¹⁷ is hydrogen or alkyl or, together with the nitrogen atom to whichthey are attached,

R¹⁶ and R¹⁷ form a heterocyclic ring;

Y is OR¹⁸ or NR¹⁹R²⁰;

R¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁹ is hydrogen or alkyl;

R²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R¹⁹ and R²⁰ form a heterocyclic ring;

R²¹ is hydrogen or alkyl;

n is 0 to 4; and

p is 0 or 1.

In a fifth aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes prior to said surgery;

wherein said gastrointestinal dysfunction is postoperative ileus; and

-   -   wherein said 4-aryl-piperidine derivative is a compound of        formula (IA):

wherein:

R¹ is hydrogen or alkyl;

R² is hydrogen, alkyl, or alkenyl;

R³ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁴ is hydrogen, alkyl, or alkenyl;

A is OR⁵ or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substitutedalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, togetherwith the nitrogen atom to which they are attached, R⁶ and R⁷ form aheterocyclic ring;

B is

C(═O)W or NR⁸R⁹;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl,cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R⁸ and R⁹ form a heterocyclic ring;

W is OR¹⁰, NR¹¹R¹², or OE;

R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, togetherwith the nitrogen atom to which they are attached, R¹¹ and R¹² form aheterocyclic ring;

E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴;

R¹³ is alkyl substituted alkylene;

R¹⁴ is alkyl;

D is OR¹⁵ or NR¹⁶R¹⁷;

R¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl;

R¹⁷ is hydrogen or alkyl or, together with the nitrogen atom to whichthey are attached, R¹⁶ and R¹⁷ form a heterocyclic ring;

Y is OR¹⁸ or NR¹⁹R²⁰;

R¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁹ is hydrogen or alkyl;

-   -   R²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,        cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,        aralkyl, heteroaryl, or heteroarylalkyl or, together with the        nitrogen atom to which they are attached, R¹⁹ and R²⁰ form a        heterocyclic ring;

R²¹ is hydrogen or alkyl;

n is 0 to 4; and

p is 0 or 1.

In a sixth aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes after said administration;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is a compound of formula (IA):

wherein:

R¹ is hydrogen or alkyl;

R² is hydrogen, alkyl, or alkenyl;

R³ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁴ is hydrogen, alkyl, or alkenyl;

A is OR⁵ or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substitutedalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, togetherwith the nitrogen atom to which they are attached, R⁶ and R⁷ form aheterocyclic ring;

B is

C(═O)W or NR⁸R⁹;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl,cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R⁸ and form R⁹ a heterocyclic ring;

W is OR¹⁰, NR¹¹R¹², or OE;

R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, togetherwith the nitrogen atom to which they are attached, R¹¹ and R¹² form aheterocyclic ring;

E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴;

R¹³ is alkyl substituted alkylene;

R¹⁴ is alkyl;

D is OR¹¹ or NR¹⁶R¹⁷;

R¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl;

R¹⁷ is hydrogen or alkyl or, together with the nitrogen atom to whichthey are attached, R¹⁶ and R¹⁷ form a heterocyclic ring;

Y is OR¹⁸ or NR¹⁹R²⁰;

R¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁹ is hydrogen or alkyl;

R²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R¹⁹ and R²⁰ form a heterocyclic ring;

R²¹ is hydrogen or alkyl;

n is 0 to 4; and

p is 0 or 1.

These and other aspects of the invention will become more apparent fromthe following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the free plasma concentration of alvimopan (12 mg dose) asa function of time.

FIG. 2 shows GI score as a function of log of plasma concentrationsmeasured as AUC (τ) (in ng-ml/hr) with a GI score measured byradio-opaque markers in subjects given loperamide with either placebo orone of three doses of I.V. alvimopan (0.1 mg b.i.d, 0.45 mg b.i.d., and1 mg b.i.d.) selected to target different plasma concentrations (4.5,20, and 45 ng/ml, respectively).

DETAILED DESCRIPTION OF THE INVENTION

The methods of the present invention are directed to treating andpreventing gastrointestinal dysfunction, particularly postoperativeileus and post-partum ileus, in a patient undergoing surgery. Differenttypes of ileus may be treated and/or prevented using the methods of thepresent invention. The present methods are particularly suitable fortreating and/or preventing postoperative ileus and post-partum ileus.“Postoperative ileus,” which may follow surgery such as laparotomy, maybe characterized by such symptoms as, for example, obstruction of thegut, particularly in the colon, resulting in nausea, vomiting, lack ofpassage of flatus and/or stools, abdominal distention and lack of bowelsounds. This condition generally lasts from about 3 to about 5 days, butmay endure longer, including up to about one week. Longer durations aregenerally characteristic of a more severe form of ileus, termedpost-surgical paralytic ileus, which may affect other portions of the GItract in addition to the colon. “Post-partum ileus” generally refers toobstruction of the gut, particularly the colon, following parturition.Both natural and surgically-assisted procedures during parturition maylead to post-partum ileus treated by the present invention. Symptoms ofpost-partum ileus and postoperative ileus are similar.

Error! Bookmark not Defined.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

As used herein, “alkyl” refers to an optionally substituted, saturatedstraight, branched, or cyclic hydrocarbon having from about 1 to about20 carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 1 to about 8carbon atoms, herein referred to as “lower alkyl”, being preferred.“Branched” refers to an alkyl group in which a lower alkyl group, suchas methyl, ethyl, or propyl, is attached to a linear alkyl chain. Incertain preferred embodiments, the alkyl group is a C₁-C₅ alkyl group,i.e., a branched or linear alkyl group having from 1 to about 5 carbons.In other preferred embodiments, the alkyl group is a C₁-C₃ alkyl group,i.e., a branched or linear alkyl group having from 1 to about 3 carbons.Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl,nonyl, and decyl. “Lower alkyl” refers to an alkyl group having 1 toabout 6 carbon atoms. Preferred alkyl groups include the lower alkylgroups of 1 to about 3 carbons. Alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl,cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl, 2,2-dimethylbutyl,and 2,3-dimethylbutyl.

As used herein, “alkylene” refers to a bivalent alkyl radical having thegeneral formula —(CH₂)_(n)—, where n is 1 to 10, and all combinationsand subcombinations of ranges therein. The alkylene group may bestraight, branched or cyclic. Non-limiting examples include methylene,methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—(CH₂)₃—),trimethylene, pentamethylene, and hexamethylene. There may be optionallyinserted along the alkylene group one or more oxygen, sulfur oroptionally substituted nitrogen atoms, wherein the nitrogen substituentis alkyl as described previously. Alkylene groups can be optionallysubstituted. The term “lower alkylene” herein refers to those alkylenegroups having from about 1 to about 6 carbon atoms. Preferred alkylenegroups have from about 1 to about 4 carbons.

As used herein, “aralkylene” refers to a bivalent alkyl radical havingthe general formula —(CH₂)_(n)—, wherein any one of the hydrogens on thealkylene radical is replaced by an aryl group, and where n is 1 to 10.Aralkylene groups can be optionally substituted. Non-limiting examplesinclude phenylmethylene, 2-phenyltrimethylene,3-(p-anisyl)-pentamethylene, and2-(m-trifluromethylphenyl)-hexamethylene. Aralkylene groups can besubstituted or unsubstituted. The term “lower aralkylene” herein refersto those aralkylene groups having from about 1 to about 6 carbon atomsin the alkylene portion of the aralkylene group.

As used herein, “alkenyl” refers to a monovalent alkyl radicalcontaining at least one carbon-carbon double bond and having from 2 toabout 10 carbon atoms in the chain, and all combinations andsubcombinations of ranges therein. Alkenyl groups can be optionallysubstituted. In certain preferred embodiments, the alkenyl group is aC₂-C₁₀ alkyl group, i.e., a branched or linear alkenyl group having from2 to about 10 carbons. In other preferred embodiments, the alkenyl groupis a C₂-C₆ alkenyl group, i.e., a branched or linear alkenyl grouphaving from 2 to about 6 carbons. In still other preferred embodiments,the alkenyl group is a C₃-C₁₀ alkenyl group, i.e., a branched or linearalkenyl group having from about 3 to about 10 carbons. In yet otherpreferred embodiments, the alkenyl group is a C₂-C₅ alkenyl group, i.e.,a branched or linear alkenyl group having from 2 to about 5 carbons.Exemplary alkenyl groups include, for example, vinyl, propenyl, butenyl,pentenyl hexenyl, heptenyl, octenyl, nonenyl and decenyl groups.

As used herein, the term “alkenylene” refers to an alkylene groupcontaining at least one carbon-carbon double bond. Exemplary alkenylenegroups include, for example, ethenylene (—CH═CH—) and propenylene(—CH═CHCH₂—). Preferred alkenylene groups have from 2 to about 4carbons.

As used herein, “aryl” refers to an optionally substituted, mono-, di-,tri-, or other multicyclic aromatic ring system having from about 5 toabout 50 carbon atoms (and all combinations and subcombinations ofranges and specific numbers of carbon atoms therein), with from about 6to about 10 carbons being preferred. Non-limiting examples include, forexample, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

As used herein, “aralkyl” refers to alkyl radicals bearing an arylsubstituent and have from about 6 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 6 to about 10 carbon atoms beingpreferred. Aralkyl groups can be optionally substituted in either thearyl or alkyl portions. Non-limiting examples include, for example,phenylmethyl(benzyl), diphenylmethyl, triphenylmethyl, phenylethyl,diphenylethyl and 3-(4-methylphenyl)propyl.

As used herein, “heteroaryl” refers to an optionally substituted, mono-,di-, tri-, or other multicyclic aromatic ring system that includes atleast one, and preferably from 1 to about 4 sulfur, oxygen, or nitrogenheteroatom ring members. Heteroaryl groups can have, for example, fromabout 3 to about 50 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 4 to about 10 carbons being preferred. Non-limitingexamples of heteroaryl groups include, for example, pyrryl, furyl,pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl,carbazolyl, benzimidazolyl, and isoxazolyl.

As used herein, “cycloalkyl” refers to an optionally substituted, alkylgroup having one or more rings in their structures having from about 3to about 20 carbon atoms (and all combinations and subcombinations ofranges and specific numbers of carbon atoms therein), with from about 3to about 10 carbon atoms being preferred, with from about 3 to about 8carbon atoms being more preferred, with from about 3 to about 6 carbonatoms being even more preferred. Multi-ring structures may be bridged orfused ring structures. The cycloalkyl group may be optionallysubstituted with, for example, alkyl, preferably C₁-C₃ alkyl, alkoxy,preferably C₁-C₃ alkoxy, or halo. Non-limiting examples include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptylcyclooctyl, and adamantyl.

As used herein, “cycloalkyl-substituted alkyl” refers to a linear alkylgroup, preferably a lower alkyl group, substituted at a terminal carbonwith a cycloalkyl group, preferably a C₃-C₈ cycloalkyl group.Non-limiting examples include, for example, cyclohexylmethyl,cyclohexylethyl, cyclopentylethyl, cyclopentylpropyl, cyclopropylmethyland the like.

As used herein, “cycloalkenyl” refers to an olefinically unsaturatedcycloalkyl group having from about 4 to about 10 carbons, and allcombinations and subcombinations of ranges therein. In preferredembodiments, the cycloalkenyl group is a C₅-C₈ cycloalkenyl group, i.e.,a cycloalkenyl group having from about 5 to about 8 carbons.

As used herein, “alkylcycloalkyl” refers to an optionally substitutedring system comprising a cycloalkyl group having one or more alkylsubstituents. Non-limiting examples include, for example,alkylcycloalkyl groups include 2-methylcyclohexyl,3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and4-methyldecahydronaphthalenyl.

As used herein, “heteroaralkyl” refers to an optionally substituted,heteroaryl substituted alkyl radicals having from about 2 to about 50carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 6 to about 25carbon atoms being preferred. Non-limiting examples include2-(1H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and3-(pyrimidin-2-yl)-2-methylcyclopentanyl.

As used herein, “heterocycloalkyl” refers to an optionally substituted,mono-, di-, tri-, or other multicyclic aliphatic ring system thatincludes at least one, and preferably from 1 to about 4 sulfur, oxygen,or nitrogen heteroatom ring members. Heterocycloalkyl groups can havefrom about 3 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 4 to about 10 carbons being preferred. Theheterocycloalkyl group may be unsaturated, and may also be fused toaromatic rings. Non-limiting examples include, for example,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, piperazinyl, morpholinyl, piperadinyl, decahydroquinolyl,octahydrochromenyl, octahydro-cyclopenta[c]pyranyl,1,2,3,4,-tetrahydroquinolyl, octahydro-[2]pyrindinyl,decahydro-cycloocta[c]furanyl, and imidazolidinyl.

As used herein, the term “spiroalkyl” refers to an optionallysubstituted, alkylene diradical, both ends of which are bonded to thesame carbon atom of the parent group to form a spirocyclic group. Thespiroalkyl group, taken together with its parent group, as hereindefined, has 3 to 20 ring atoms. Preferably, it has 3 to 10 ring atoms.Non-limiting examples of a spiroalkyl group taken together with itsparent group include 1-(1-methyl-cyclopropyl)-propan-2-one,2-(1-phenoxy-cyclopropyl)-ethylamine, and 1-methyl-spiro[4.7]dodecane.

As used herein, the term “alkoxy” refers to an optionally substitutedalkyl-O— group wherein alkyl is as previously defined. Non-limitingexamples include, for example, include methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, and heptoxy.

As used herein, the term “aryloxy” refers to an optionally substitutedaryl-O— group wherein aryl is as previously defined. Non-limitingexamples include, for example, phenoxy and naphthoxy.

As used herein, the term “aralkoxy” refers to an optionally substitutedaralkyl-O— group wherein aralkyl is as previously defined. Non-limitingexamples include, for example, benzyloxy, 1-phenylethoxy,2-phenylethoxy, and 3-naphthylheptoxy.

As used herein, the term “aryloxyaryl” refers to an aryl group with anaryloxy substituent wherein aryloxy and aryl are as previously defined.Aryloxyaryl groups can be optionally substituted. Non-limiting examplesinclude, for example, phenoxyphenyl, and naphthoxyphenyl.

As used herein, the term “heteroarylaryl” refers to an aryl group with aheteroaryl substituent wherein heteroaryl and aryl are as previouslydefined. Heteroarylaryl groups can be optionally substituted.Non-limiting examples include, for example, 3-pyridylphenyl,2-quinolylnaphthalenyl, and 2-pyrrolylphenyl.

As used herein, the term “alkoxyaryl” refers to an aryl group bearing analkoxy substituent wherein alkoxy and aryl are as previously defined.Alkoxyaryl groups can be optionally substituted. Non-limiting examplesinclude, for example, para-anisyl, meta-t-butoxyphenyl, andmethylendioxyphenyl.

As used herein, the term “carbon chain of said alkoxy interrupted by anitrogen atom” refers to a carbon chain of an alkoxy group, wherein anitrogen atom has been inserted between two adjacent carbon atoms of thecarbon chain and wherein alkoxy is as previously defined. Both thealkoxy group and the nitrogen atom can be optionally substituted.Exemplary groups include —OCH₂CH₂N(CH₃)CH₂CH₃ and —OCH₂CH₂NHCH₃.

As used herein, the term “heterocycloalkylheteroaryl” refers to anheteroaryl group with a heterocycloalkyl substituent whereinheterocycloalkyl and heteroaryl are as previously defined.Heterocycloalkylheteroaryl groups can be optionally substituted.Exemplary heterocycloalkylheteroaryl groups include3-[N-morpholinyl]pyridine and 3-[2-piperidinyl]pyridine.

As used herein, the term “heteroarylheteroaryl” refers to a heteroarylgroup with a heteroaryl substituent wherein heteroaryl is as previouslydefined. Heteroarylherteroaryl groups can be optionally substituted.Exemplary heteroarylheteroaryl groups include 4-[3-pyridyl]pyridine and2-[2-quinolyl]quinuclidine.

As used herein, the term “aralkoxyaryl” refers to an aryl group with anaralkoxy substituent wherein aralkoxy and aryl are as previouslydefined. Aralkoxyaryl groups can be optionally substituted. Exemplaryaralkoxyaryl groups include benzyloxyphenyl and meta-toluenyloxyphenyl.

As used herein, the term “arylheteroaryl” refers to a heteroaryl groupwith an aryl substituent wherein aryl and heteroaryl are as previouslydefined. Arylheteroaryl groups can be optionally substituted. Exemplaryarylheteroaryl groups include 3-phenylpyridyl and2-naphthalenylquinolinyl.

As used herein, the term “alkoxyheteroaryl” refers to an heteroarylgroup with an alkoxy substituent wherein alkoxy and heteroaryl are aspreviously defined. Alkoxyheteroaryl groups can be optionallysubstituted. Exemplary alkoxyheteroaryl groups include 2-methoxypyridineand 6-n-propoxyquinoline.

As used herein, “bicycloalkyl” refers to an optionally substituted,alkyl group having two bridged rings in its structure and having fromabout 7 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 7 to about 15 carbon atoms being preferred. Exemplarybicycloalkyl-ring structures include, but are not limited to, norbornyl,bornyl, [2.2.2]-bicyclooctyl, cis-pinanyl, trans-pinanyl, camphanyl,iso-bornyl, and fenchyl.

As used herein, “bicycloalkenyl” refers to an optionally substituted,alkenyl group having two bridged rings in its structure and having fromabout 7 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 7 to about 15 carbon atoms being preferred. Exemplarybicycloalkenyl-ring structures include, but are not limited to,bicyclo[2.2.1]hept-5-en-2-yl, bornenyl, [2.2.2]-bicyclooct-5-en-2-yl,α-pinenyl, β-pinenyl, camphenyl, and fenchyl.

As used herein, “carboxy” refers to a —C(═O)OH group.

As used herein, “alkanoyl” refers to a —C(═O)-alkyl group, wherein alkylis as previously defined. Exemplary alkanoyl groups includeacetyl(ethanoyl), n-propanoyl, n-butanoyl, 2-methylpropanoyl,n-pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 2,2-dimethylpropanoyl,heptanoyl, decanoyl, and palmitoyl.

As used herein, “alkoxy-alkyl” refers to an alkyl-O-alkyl group wherealkyl is as previously described.

As used herein, “heterocyclic” refers to a monocyclic or multicyclicring system carbocyclic radical containing from about 4 to about 10members, and all combinations and subcombinations of ranges therein,wherein one or more of the members is an element other than carbon, forexample, nitrogen, oxygen or sulfur. The heterocyclic group may bearomatic or nonaromatic. Non-limiting examples include, for example,pyrrole and piperidine groups.

As used herein, “halo” refers to fluoro, chloro or bromo.

Typically, substituted chemical moieties include one or moresubstituents that replace hydrogen. Exemplary substituents include, forexample, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl,alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl,heterocycloalkyl, hydroxyl (—OH), nitro (—NO₂), cyano (—CN), amino(—NH₂), —N-substituted amino (—NHR″), —N,N-disubstituted amino(—N(R″)R″), carboxyl (—COOH), —C(═O)R″, —OR″, —C(═O)OR″, —NHC(═O)R″,aminocarbonyl (—C(═O)NH₂), —N-substituted aminocarbonyl (—C(═O)NHR″),—N,N-disubstituted aminocarbonyl (—C(═O)N(R″)R″), thiol, thiolato (SR″),sulfonic acid (SO₃H), phosphoric acid (PO₃H), S(═O)₂R¹¹, S(═O)₂NH₂,S(═O)₂NHR″, S(═O)₂NR″R″, NHS(═O)₂R″, NR″S(═O)₂R″, CF₃, CF₂CF₃,NHC(═O)NHR″, NHC(═O)NR″R″, NR″C(═O)NHR″, NR″C(═O)NR″R″, NR″C(═O)R″ andthe like. In relation to the aforementioned substituents, each moiety R″can be, independently, any of H, alkyl, cycloalkyl, alkenyl, aryl,aralkyl, heteroaryl, or heterocycloalkyl, for example.

As used herein, the phrase “to substantially saturate” refers to theproviding sufficient compound to the patient to achieve a maximum free(unbound) concentrations greater than or equal to 10-fold above the Kito produce greater than 91% receptor occupancy, as defined in Copeland,R. E., Enzymes. A Practical Introduction to Structure, Mechanism, andData Analysis, 2^(nd) Edition, (New York: Wiley-VCH, 2000), page 88, thedisclosure of which is incorporated herein by reference.

As used herein, the term “surgery” refers to any methodical action ofthe hand, or of the hand with instruments, on a patient, to produce acurative or remedial effect, and specifically includes Caesarian birthsand sterilizations.

As used herein, the term “side effect” refers to a consequence otherthan the one(s) for which an agent or measure is used, as the adverseeffects produced by a drug, especially on a tissue or organ system otherthen the one sought to be benefited by its administration. In the case,for example, of the treatment of gastrointestinal dysfunction, such asthe treatment of postoperative ileus, the term “side effect” may referto such conditions as, for example, nausea, vomiting, diarrhea, andcombinations thereof.

As used herein, “dosage unit” refers to physically discrete units suitedas unitary dosages for the particular individual to be treated. Eachunit may contain a predetermined quantity of active compound(s)calculated to produce the desired therapeutic effect(s) in associationwith the required pharmaceutical carrier. The specification for thedosage unit forms of the invention may be dictated by (a) the uniquecharacteristics of the active compound(s) and the particular therapeuticeffect(s) to be achieved, and (b) the limitations inherent in the art ofcompounding such active compound(s).

As used herein, “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms that are, within the scopeof sound medical judgment, suitable for contact with the tissues ofhuman beings and animals without excessive toxicity, irritation,allergic response, or other problem complications commensurate with areasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like. These physiologically acceptable salts are prepared bymethods known in the art, e.g., by dissolving the free amine bases withan excess of the acid in aqueous alcohol, or neutralizing a freecarboxylic acid with an alkali metal base such as a hydroxide, or withan amine.

Compounds described herein throughout, can be used or prepared inalternate forms. For example, many amino-containing compounds can beused or prepared as an acid addition salt. Often such salts improveisolation and handling properties of the compound. For example,depending on the reagents, reaction conditions and the like, compoundsas described herein can be used or prepared, for example, as theirhydrochloride or tosylate salts. Isomorphic crystalline forms, allchiral and racemic forms, N-oxide, hydrates, solvates, and acid salthydrates, are also contemplated to be within the scope of the presentinvention.

Certain acidic or basic compounds of the present invention may exist aszwitterions. All forms of the compounds, including free acid, free baseand zwitterions, are contemplated to be within the scope of the presentinvention. It is well known in the art that compounds containing bothamino and carboxyl groups often exist in equilibrium with theirzwitterionic forms. Thus, any of the compounds described hereinthroughout that contain, for example, both amino and carboxyl groups,also include reference to their corresponding zwitterions.

As used herein, “patient” refers to animals, including mammals,preferably humans.

As used herein, “prodrug” refers to compounds specifically designed tomaximize the amount of active species that reaches the desired site ofreaction that are of themselves typically inactive or minimally activefor the activity desired, but through biotransformation are convertedinto biologically active metabolites.

As used herein, “stereoisomers” refers to compounds that have identicalchemical constitution, but differ as regards the arrangement of theatoms or groups in space.

As used herein, “N-oxide” refers to compounds wherein the basic nitrogenatom of either a heteroaromatic ring or tertiary amine is oxidized togive a quaternary nitrogen bearing a positive formal charge and anattached oxygen atom bearing a negative formal charge.

As used herein, “hydrate” refers to a compound of the present inventionwhich is associated with water in the molecular form, i.e., in which theH—OH bond is not split, and may be represented, for example, by theformula R.H₂O, where R is a compound of the invention. A given compoundmay form more than one hydrate including, for example, monohydrates(R.H₂O) or polyhydrates (R.nH₂O wherein n is an integer >1) including,for example, dihydrates (R.2H₂O), trihydrates (R.3H₂O), and the like, orhemihydrates, such as, for example, R.n/2H₂O, R.n/3H₂O, R.n/4H₂O and thelike wherein n is an integer.

As used herein, “solvate” refers to a compound of the present inventionwhich is associated with solvent in the molecular form, i.e., in whichthe solvent is coordinatively bound, and may be represented, forexample, by the formula R.(solvent), where R is a compound of theinvention. A given compound may form more than one solvate including,for example, monosolvates (R.(solvent)) or polysolvates (R.n(solvent))wherein n is an integer >1) including, for example, disolvates(R.2(solvent)), trisolvates (R.3(solvent)), and the like, orhemisolvates, such as, for example, R.n/2(solvent), R.n/3(solvent),R.n/4(solvent) and the like wherein n is an integer. Solvents hereininclude mixed solvents, for example, methanol/water, and as such, thesolvates may incorporate one or more solvents within the solvate.

As used herein, “acid salt hydrate” refers to a complex that may beformed through association of a compound having one or more basemoieties with at least one compound having one or more acid moieties orthrough association of a compound having one or more acid moieties withat least one compound having one or more base moieties, said complexbeing further associated with water molecules so as to form a hydrate,wherein said hydrate is as previously defined and R represents thecomplex herein described above.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The piperidines derivatives useful in the methods of the invention asillustrated in formula (IA) can occur as the trans and cisstereochemical isomers at the 3- and 4-positions of the piperidine ring.The term “trans” as used herein refers, for example, in formula (IA) tothe R² substituent being on the opposite side of the R⁴ substituent,whereas in the “cis” isomer, the R² substituent and the R⁴ substituentare on the same side of the ring. The present invention contemplates theindividual stereoisomers, as well as racemic mixtures. In the mostpreferred compounds of formula (IA), the R² substituent and the R⁴substituent are in the “trans” orientation on the piperidine.

In addition to the “cis” and “trans” orientation of the R² substituentand the R⁴ substituent of formula (IA), the absolute stereochemistry ofthe carbon atoms bearing R² substituent and the R⁴ substituent offormula (IA) is also defined as using the commonly employed “R” and “S”definitions (Orchin et al., The Vocabulary of Organic Chemistry, JohnWiley and Sons, Inc., 1981, page 126, which is incorporated herein byreference). The preferred compounds of the present invention are inwhich the configuration of both the R² substituent and the R⁴substituents of formula (IA) on the piperidine ring are “R.”

Furthermore, asymmetric carbon atoms may be introduced into the moleculedepending on the structure of R⁴. As such, these classes of compoundscan exist as the individual “R” or “S” stereoisomers at these chiralcenters, or the racemic mixture of the isomers, and all are contemplatedas within the scope of the present invention. Preferably, asubstantially pure stereoisomer of the compounds of this invention isused, i.e., an isomer in which the configuration at the chiral center is“R” or “S”, i.e., those compounds in which the configuration at thethree chiral centers are preferably 3R, 4R, S or 3R, 4R, R.

As used herein, “peripheral” or “peripherally-acting” refers to an agentthat acts outside of the central nervous system.

As used herein, “centrally-acting” refers to an agent that acts withinthe central nervous system (CNS).

In certain preferred embodiments, the methods may involve a peripheralopioid antagonist compound. The term “peripheral” designates that thecompound acts primarily on physiological systems and components externalto the central nervous system. In preferred form, the peripheral opioidantagonist compounds employed in the methods of the present inventionexhibit high levels of activity with respect to peripheral tissue, suchas, gastrointestinal tissue, while exhibiting reduced, and preferablysubstantially no, CNS activity. The phrase “substantially no CNSactivity,” as used herein, means that less than about 20% of thepharmacological activity of the compounds employed in the presentmethods is exhibited in the CNS, preferably less than about 15%, morepreferably less than about 10%, even more preferably less than about 5%and most preferably 0% of the pharmacological activity of the compoundsemployed in the present methods is exhibited in the CNS.

Furthermore, it is preferred in certain embodiments of the inventionthat the compound of formula (IA) does not substantially cross theblood-brain barrier and thereby interfere with the receptors in the CNS.The phrase “does not substantially cross,” as used herein, means thatless than about 20% by weight of the compound employed in the presentmethods crosses the blood-brain barrier, preferably less than about 15%by weight, more preferably less than about 10% by weight, even morepreferably less than about 5% by weight and most preferably 0% by weightof the compound crosses the blood-brain barrier.

The methods of the present invention are directed to treating andpreventing gastrointestinal dysfunction in a patient undergoing surgeryor other biological stress, including the birth process. Suchgastrointestinal dysfunction includes postoperative ileus andpost-partum ileus.

The methods of the present invention may further employ one or moreother active ingredients that may be conventionally employed inpreventing or treating gastrointestinal dysfunction. Such conventionalingredients include, for example, laxatives, fiber, stool softeners, orbowel stimulants. Typical or conventional ingredients that may beincluded are described, for example, in the Physicians' Desk Reference,2003, the disclosure of which is hereby incorporated herein byreference, in its entirety. Other optional components that may beemployed in the methods and compositions of the present invention, inaddition to those exemplified above, would be readily apparent to one ofordinary skill in the art, once armed with the teachings of the presentdisclosure.

Suitable 4-aryl-piperidine derivatives and a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide and an isomorphic crystalline form thereof.Preferred 4-aryl-piperidine derivatives include, for example, thecompounds disclosed in U.S. Pat. No. 5,250,542; U.S. Pat. No. 5,159,081;U.S. Pat. No. 5,270,328; and U.S. Pat. No. 5,434,171, U.S. Pat. No.6,451,806 and U.S. Pat. No. 6,469,030, the disclosures of which arehereby incorporated herein by reference, in their entireties.

In a first aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the freeconcentration in the plasma of said patient of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is sufficient to substantiallysaturate the μ opioid receptors in the gastrointestinal tract of saidpatient;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is sufficient to achieve substantially complete saturation of μopioid receptors in the gastrointestinal tract of said patient;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.

In a second aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes prior to said surgery;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.

In a third aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes after said administration;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.

In preferred embodiments, the[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid is in hydrate form, more preferably,[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid dihydrate, even more preferably in substantially pure isomericform, most especially[[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid dihydrate (alvimopan).

In a fourth aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the freeconcentration in the plasma of said patient of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is sufficient to substantiallysaturate the μ opioid receptors in the gastrointestinal tract of saidpatient;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is sufficient to achieve substantially complete saturation of μopioid receptors in the gastrointestinal tract of said patient;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is a compound of formula (IA):

-   -   wherein:

R¹ is hydrogen or alkyl;

R² is hydrogen, alkyl, or alkenyl;

R³ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁴ is hydrogen, alkyl, or alkenyl;

A is OR⁵ or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substitutedalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, togetherwith the nitrogen atom to which they are attached, R⁶ and R⁷ form aheterocyclic ring;

B is

C(═O)W or NR⁸R⁹;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl,cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R⁸ and R⁹ form a heterocyclic ring;

W is OR¹⁰, NR¹¹R¹², or OE;

R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, togetherwith the nitrogen atom to which they are attached, R¹¹ and R¹² form aheterocyclic ring;

E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴;

R¹³ is alkyl substituted alkylene;

R¹⁴ is alkyl;

D is OR¹⁵ or NR¹⁶R¹⁷;

R¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl;

R¹⁷ is hydrogen or alkyl or, together with the nitrogen atom to whichthey are attached, R¹⁶ and R¹⁷ form a heterocyclic ring;

Y is OR¹⁸ or NR¹⁹R²⁰;

R¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁹ is hydrogen or alkyl;

R²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R¹⁹ and R²⁰ form a heterocyclic ring;

R²¹ is hydrogen or alkyl;

n is 0 to 4; and

p is 0 or 1.

In a fifth aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes prior to said surgery;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is a compound of formula (IA):

wherein:

R¹ is hydrogen or alkyl;

R² is hydrogen, alkyl, or alkenyl;

R³ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁴ is hydrogen, alkyl, or alkenyl;

A is OR⁵ or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substitutedalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, togetherwith the nitrogen atom to which they are attached, R⁶ and R⁷ form aheterocyclic ring;

B is

C(═O)W or NR⁸R⁹;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl,cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R⁸ and R⁹ form a heterocyclic ring;

W is OR¹⁰, NR¹¹R¹², or OE;

R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, togetherwith the nitrogen atom to which they are attached, R¹¹ and R¹² form aheterocyclic ring;

E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴;

R¹³ is alkyl substituted alkylene;

R¹⁴ is alkyl;

D is OR¹⁵ or NR¹⁶R¹⁷;

R¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl;

R¹⁷ is hydrogen or alkyl or, together with the nitrogen atom to whichthey are attached, R¹⁶ and R¹⁷ form a heterocyclic ring;

Y is OR¹⁸ or NR¹⁹R²⁰;

R¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁹ is hydrogen or alkyl;

R²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R¹⁹ and R²⁰ form a heterocyclic ring;

R²¹ is hydrogen or alkyl;

n is 0 to 4; and

p is 0 or 1.

In a sixth aspect, the present invention is directed, in part, tomethods of treating or preventing gastrointestinal dysfunction in apatient undergoing surgery, comprising the step of:

administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof;

in a manner so as to obtain a pharmacokinetic profile wherein the plasmaor whole blood concentration of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof reaches a maximum concentration fromabout 30 minutes to about 120 minutes after said administration;

wherein said gastrointestinal dysfunction is postoperative ileus; and

wherein said 4-aryl-piperidine derivative is a compound of formula (IA):

wherein:

R¹ is hydrogen or alkyl;

R² is hydrogen, alkyl, or alkenyl;

R³ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁴ is hydrogen, alkyl, or alkenyl;

A is OR⁵ or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substitutedalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, togetherwith the nitrogen atom to which they are attached, R⁶ and R⁷ form aheterocyclic ring;

B is

C(═O)W or NR⁸R⁹;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl,cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl;heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R⁸ and R⁹ form a heterocyclic ring;

W is OR¹⁰, NR¹¹R¹², or OE;

R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, togetherwith the nitrogen atom to which they are attached, R¹¹ and R¹² form aheterocyclic ring;

E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴;

R¹³ is alkyl substituted alkylene;

R¹⁴ is alkyl;

D is OR¹⁵ or NR¹⁶R¹⁷;

R¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl;

R¹⁷ is hydrogen or alkyl or, together with the nitrogen atom to whichthey are attached,

R¹⁶ and R¹⁷ form a heterocyclic ring;

Y is OR¹⁸ or NR¹⁹R²⁰;

R¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl;

R¹⁹ is hydrogen or alkyl;

R²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl or, together with the nitrogen atom towhich they are attached, R¹⁹ and R²⁰ form a heterocyclic ring;

R²¹ is hydrogen or alkyl;

n is 0 to 4; and

p is 0 or 1.

In preferred embodiments, the compound of formula (IA) is a trans3,4-isomer.

In certain embodiments employing compounds of formula (IA), it ispreferred that

-   -   R¹ is hydrogen;    -   R² is alkyl;    -   n is 1 or 2;    -   R³ is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl; and    -   R⁴ is alkyl.

In certain embodiments employing compounds of formula (IA), it ispreferred that

-   -   A is OR⁵; and    -   R⁵ is hydrogen or alkyl.

In certain embodiments employing compounds of formula (IA), it ispreferred that

-   -   A is NR⁶R⁷;    -   R⁶ is hydrogen;    -   R⁷ is alkylene substituted B; and    -   B is C(O)W.

In certain embodiments employing compounds of formula (IA), it ispreferred that

-   -   R⁷ is (CH₂)_(q)—B;    -   q is about 1 to about 3;    -   W is OR¹⁰; and    -   R¹⁰ is hydrogen, alkyl, phenyl-substituted alkyl, cycloalkyl or        cycloalkyl-substituted alkyl.

In certain embodiments including compounds of formula (IA), it ispreferred that

-   -   W is NR¹¹R¹²    -   R¹¹ is hydrogen or alkyl; and    -   R¹² is hydrogen, alkyl or alkylene substituted C(═O)Y.

In certain embodiments employing compounds of formula (IA), it ispreferred that

-   -   R¹² is (CH₂)_(m)C(O)Y;    -   m is 1 to 3;    -   Y is OR¹⁸ or NR¹⁹R²⁰; and    -   R¹⁸, R¹⁹ and R²⁰ are independently hydrogen or alkyl.

In certain embodiments employing compounds of formula (IA), it ispreferred that

-   -   W is OE;    -   E is CH₂C(═O)D;    -   D is OR¹⁵ or NR¹⁶R¹⁷;    -   R¹⁵ is hydrogen or alkyl;    -   R¹⁶ is methyl or benzyl; and    -   R¹⁷ is hydrogen.

In certain embodiments employing compounds of formula (IA), it ispreferred that

-   -   W is OE;    -   E is R¹³OC(═O)R¹⁴;    -   R¹³ is —CH(CH₃)— or —CH(CH₂CH₃)—; and    -   R¹⁴ is alkyl.

In certain embodiments including compounds of formula (IA), it ispreferred that p is 1.

In certain embodiments employing compounds of formula (IA), it ispreferred that the configuration at positions 3 and 4 of the piperidinering is each R.

Preferred compounds of formula (IA) include:

-   -   Q-CH₂CH(CH₂(C₆H₅))C(O)OH,    -   Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)OCH₂CH₃,    -   Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)OH,    -   Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)NHCH₃,    -   Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)NHCH₂CH₃,    -   G-NH(CH₂)₂C(O)NH₂,    -   G-NH(CH₂)₂C(O)NHCH₃,    -   G-NHCH₂C(O)NH₂,    -   G-NHCH₂C(O)NHCH₃,    -   G-NHCH₂C(O)NHCH₂CH₃,    -   G-NH(CH₂)₃C(O)OCH₂CH₃,    -   G-NH(CH₂)₃C(O)NHCH₃,    -   G-NH(CH₂)₂C(O)OH,    -   G-NH(CH₂)₃C(O)OH,    -   Q-CH₂CH(CH₂(C₆H₁₁))C(O)NHCH₂C(O)OH,    -   Q-CH₂CH(CH₂(C₆H₁₁))C(O)NH(CH₂)₂C(O)OH,    -   Q-CH₂CH(CH₂(C₆H₁₁))C(O)NH(CH₂)₂C(O)NH₂,    -   Z—NHCH₂C(O)OCH₂CH₃,    -   Z—NHCH₂C(O)OH,    -   Z—NHCH₂C(O)NH₂,    -   Z—NHCH₂C(O)N(CH₃)₂,    -   Z—NHCH₂C(O)NHCH(CH₃)₂,    -   Z—NHCH₂C(O)OCH₂CH(CH₃)₂,    -   Z—NH(CH₂)₂C(O)OCH₂(C₆H₅),    -   Z—NH(CH₂)C(O)OH,    -   Z—NH(CH₂)₂C(O)NHCH₂CH₃,    -   Z—NH(CH₂)₃C(O)NHCH₃,    -   Z—NHCH₂C(O)NHCH₂C(O)OH,    -   Z—NHCH₂C(O)OCH₂C(O)OCH₃,    -   Z—NHCH₂C(O)O(CH₂)₄CH₃,    -   Z—NHCH₂C(O)OCH₂C(O)NHCH₃,    -   Z—NHCH₂C(O)O-(4-methoxycyclohexyl),    -   Z—NHCH₂C(O)OCH₂C(O)NHCH₂(C₆H₅) and    -   Z—NHCH₂C(O)OCH(CH₃)OC(O)CH₃;    -   wherein:

Q represents

G represents

and

Z represents

More preferred compounds of formula (IA) include:

-   -   (+)-Z—NHCH₂C(O)OH,    -   (−)-Z—NHCH₂C(O)OH,    -   (3R,4R)—Z—NHCH₂C(O)NHCH₂(C₆H₅) and    -   (3R,4R)-G-NH(CH₂)₃C(O)OH,

wherein Q, Z and G are as defined above.

Even more preferred compounds of formula (IA) include (+)-Z—NHCH₂C(O)OHand (−)-Z—NHCH₂C(O)OH, most especially (+)-Z—NHCH₂C(O)OH, where Z is asdefined above.

Even more preferred compounds of formula (IA) includeQ-CH₂CH(CH₂(C₆H₅))C(O)OH, wherein Q is as defined above. It isespecially preferred when said compound is (3R,4R,S)-Q-CH₂CH(CH₂(C₆H₅))C(O)OH.

A particularly preferred embodiment of the present invention is thecompound (+)-Z—NHCH₂C(O)OH, i.e., the compound of the following formula(II):

The compound of formula (II) has low solubility in water except at lowor high pH conditions.

In especially preferred embodiments, the compound of a formula (IA) is asubstantially pure stereoisomer.

In preferred embodiments, the methods may further comprise the step ofadministering at least one opioid to the patient. The opioid may beadministered to the patient before, during, or after surgery or anotherbiological stress. Suitable opioids include alfentanil, buprenorphine,butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone,hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine,nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene,sufentanil, and tramadol. Preferred opioids include morphine, codeine,oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, andtramadol.

The opioid component may further include one or more other activeingredients that may be conventionally employed in analgesic and/orcough-cold-antitussive combination products. Such conventionalingredients include, for example, aspirin, acetaminophen,phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and/orguaifenesin. Typical or conventional ingredients that may be included inthe opioid component are described, for example, in the Physicians' DeskReference, 1999, the disclosure of which is hereby incorporated hereinby reference, in its entirety.

In addition, the opioid component may further include one or morecompounds that may be designed to enhance the analgesic potency of theopioid and/or to reduce analgesic tolerance development. Such compoundsinclude, for example, dextromethorphan or other NMDA antagonists (Mao,M. J. et al., Pain 1996, 67, 361), L-364,718 and other CCK antagonists(Dourish, C. T. et al., Eur. J. Phannacol., 1988, 147, 469), NOSinhibitors (Bhargava, H. N. et al., Neuropeptides, 1996, 30, 219), PKCinhibitors (Bilsky, E. J. et al., J. Pharmacol. Exp. Ther. 1996, 277,484), and dynorphin antagonists or antisera (Nichols, M. L. et al.,Pain, 1997, 69, 317). The disclosures of each of the foregoing documentsare hereby incorporated herein by reference, in their entireties.

Other opioids, optional conventional opioid components, and optionalcompounds for enhancing the analgesic potency of the opioid and/or forreducing analgesic tolerance development, that may be employed in themethods and compositions of the present invention, in addition to thoseexemplified above, would be readily apparent to one of ordinary skill inthe art, once armed with the teachings of the present disclosure.

In certain preferred embodiments, the 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is administered to the patient from about 30 minutes to lessthan about 120 minutes prior to the administration of the opioid (andall combinations and subcombinations of ranges and specificadministration times therein), preferably from about 30 minutes to lessthan about 90 minutes prior to the administration of the opioid, morepreferably from about 30 minutes to less than about 60 minutes prior tothe administration of the opioid, and even more preferably from about 30minutes to less than about 45 minutes prior to the administration of theopioid.

In certain preferred embodiments, the 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is administered to the patient from about 30 minutes to lessthan about 120 minutes prior to surgery (and all combinations andsubcombinations of rangers and specific administration times therein),preferably from about 30 minutes prior to surgery to less than about 90minutes prior to surgery, more preferably from about 30 minutes prior tosurgery to less than about 60 minutes prior to surgery, and even morepreferably from about 30 minutes prior to surgery to less than about 45minutes prior to surgery.

In certain preferred embodiments, the 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is administered to the patient orally.

In certain other preferred embodiments, the 4-aryl-piperidine derivativeor stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is administered to the patient parenterally, more preferablyintravenously.

The compounds employed in the methods of the present invention may existin prodrug form. As used herein, “prodrug” is intended to include anycovalently bonded carriers that release the active parent drug, forexample, as according to formulas (IA) or other formulas or compoundsemployed in the methods of the present invention in vivo when suchprodrug is administered to a mammalian subject. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds employedin the present methods may, if desired, be delivered in prodrug form.Thus, the present invention contemplates methods of delivering prodrugs.Prodrugs of the compounds employed in the present invention, for exampleformula (IA), may be prepared by modifying functional groups present inthe compound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound.

Accordingly, prodrugs include, for example, compounds described hereinin which a hydroxy, amino, or carboxy group is bonded to any group that,when the prodrug is administered to a mammalian subject, cleaves to forma free hydroxyl, free amino, or carboxylic acid, respectively. Examplesinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups; and alkyl,carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl,benzyl, and phenethyl esters, and the like.

The compounds employed in the methods of the present invention may beprepared in a number of ways well known to those skilled in the art. Thecompounds can be synthesized, for example, using the methods describedin U.S. Pat. No. 5,250,542, U.S. Pat. No. 6,469,030, and U.S. Pat. No.6,451,806, the disclosures of which are hereby incorporated byreference, in their entireties. All processes disclosed in associationwith the present invention are contemplated to be practiced on anyscale, including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

As discussed in detail above, compounds employed in the present methodsmay contain one or more asymmetrically substituted carbon atoms, and maybe isolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare and isolate such optically active forms. For example, mixturesof stereoisomers may be separated by standard techniques including, butnot limited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from chiral startingmaterials or by deliberate synthesis of target chiral centers.

As will be readily understood, functional groups present may containprotecting groups during the course of synthesis. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred protecting groups includethe benzyloxycarbonyl group and the tert-butyloxycarbonyl group. Otherpreferred protecting groups that may be employed in accordance with thepresent invention may be described in Greene, T. W. and Wuts, P. G. M.,Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991.

As noted above, the compounds of the present invention can exist as theindividual stereoisomers. Preferably, reaction conditions are adjustedas disclosed in U.S. Pat. No. 4,581,456 or as set forth in Example 1 ofU.S. Pat. No. 5,250,542 to be substantially stereoselective and providea racemic mixture of essentially two enantiomers. These enantiomers maythen be resolved. A procedure which may be employed to prepare theresolved starting materials used in the synthesis of these compoundsincludes treating a racemic mixture ofalkyl-3,4-dimethyl-4-(3-alkoxyphenyl)piperidine with either (+)- or(−)-ditoluoyl tartaric acid to provide the resolved intermediate. Thiscompound may then be dealkylated at the 1-position with vinylchloroformate and finally converted to the desired4-(3-hydroxyphenyl)piperidine isomer.

As will be understood by those skilled in the art, the individualenantiomers of the invention can also be isolated with either (+) or(−)dibenzoyl tartaric acid, as desired, from the corresponding racemicmixture of the compounds of the invention. Preferably, the (+)-transenantiomer is obtained.

Although the (+)trans-3,4 stereoisomer is preferred, all of the possiblestereoisomers of the compounds described herein are within thecontemplated scope of the present invention. Racemic mixtures of thestereoisomers as well as the substantially pure stereoisomers are withinthe scope of the invention. The term “substantially pure,” as usedherein, refers to at least about 90 mole percent, more preferably atleast about 95 mole percent and most preferably at least about 98 molepercent of the desired stereoisomer is present relative to otherpossible stereoisomers.

The compounds employed in the methods of the present invention may beadministered by any means that results in the contact of the activeagents with the agents' site or site(s) of action in the body of apatient. The compounds may be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.For example, they may be administered as the sole active agents in apharmaceutical composition, or they can be used in combination withother therapeutically active ingredients.

The compounds are preferably combined with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice as described, for example, in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa., 1980), thedisclosures of which is hereby incorporated herein by reference, in itsentirety.

Compounds of the present invention can be administered to a mammalianhost in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, and intraperitoneal. Otheracceptable routes of administration are transepithelial includingtransdermal, transnasal, ophthalmic, sublingual and buccal; topicallyincluding ophthalmic, dermal, ocular, and rectal; nasal or pulmonaryinhalation via insufflation or aerosol; and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, it may be enclosedin hard or soft shell gelatin capsules, it may be compressed intotablets, or it may be incorporated directly with the food of the diet.For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The amount of active compound(s) in such therapeuticallyuseful compositions is from about 0.1 mg/day to about 500 mg/day ofactive compound, including all combinations, and subcombinationsthereof.

In certain preferred embodiments of the invention, said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is administered at a level of atleast about 0.75 mg/day, more preferably at a level of at least about 1mg/day, even more preferably at a level of at least about 2 mg/day, andyet even more preferably at a level of at least about 3 mg/day.

In certain preferred embodiments of the invention, said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is administered at a level of lessthan about 300 mg/day, more preferably at a level of less than about 120mg/day, even more preferably at a level of less than about 60 mg/day,and yet even more preferably at a level of less than about 30 mg/day.

The tablets, troches, pills, capsules and the like may also contain oneor more of the following: a binder, such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent, such as corn starch, potato starch, alginic acidand the like; a lubricant, such as magnesium stearate; a sweeteningagent such as sucrose, lactose or saccharin; or a flavoring agent, suchas peppermint, oil of wintergreen or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form ispreferably pharmaceutically pure and substantially non-toxic in theamounts employed. In addition, the active compound may be incorporatedinto sustained-release preparations and formulations.

The active compound may also be administered parenterally. Solutions ofthe active compounds as free bases or pharmacologically acceptable saltscan be prepared in water suitably mixed with a surfactant, such ashydroxypropylcellulose. A dispersion can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations may contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include, forexample, sterile aqueous solutions or dispersions and sterile powdersfor the extemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form is preferably sterile and fluid toprovide easy syringability. It is preferably stable under the conditionsof manufacture and storage and is preferably preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier may be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol and the like), suitable mixtures thereof, andvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating, such as lecithin, by the maintenance of therequired particle size in the case of a dispersion, and by the use ofsurfactants. The prevention of the action of microorganisms may beachieved by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.In many cases, it will be preferable to include isotonic agents, forexample, sugars or sodium chloride. Prolonged absorption of theinjectable compositions may be achieved by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the activecompounds in the required amounts, in the appropriate solvent, withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions may be prepared byincorporating the sterilized active ingredient into a sterile vehiclewhich contains the basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile powdersfor the preparation of sterile injectable solutions, the preferredmethods of preparation may include vacuum drying and the freeze-dryingtechnique that yield a powder of the active ingredient, plus anyadditional desired ingredient from the previously sterile-filteredsolution thereof.

The therapeutic compounds of this invention may be administered to apatient alone or in combination with a pharmaceutically acceptablecarrier. As noted above, the relative proportions of active ingredientand carrier may be determined, for example, by the solubility andchemical nature of the compounds, chosen route of administration andstandard pharmaceutical practice.

The dosage of the compounds of the present invention that will be mostsuitable for prophylaxis or treatment will vary with the form ofadministration, the particular compound chosen and the physiologicalcharacteristics of the particular patient under treatment. Generally,small dosages may be used initially and, if necessary, increased bysmall increments until the desired effect under the circumstances isreached. Generally speaking, oral administration may require higherdosages.

The combination products useful in the methods of this invention, suchas pharmaceutical compositions comprising 4-aryl-piperidine derivativeswith additional active ingredients, may be in any dosage form, such asthose described herein, and can also be administered in various ways, asdescribed herein. In a preferred embodiment, the combination products ofthe invention are formulated together, in a single dosage form (that is,combined together in one capsule, tablet, powder, or liquid, etc.). Whenthe combination products are not formulated together in a single dosageform, the 4-aryl-piperidine derivative and additional active ingredientmay be administered at the same time or simultaneously (that is,together), or in any order. When not administered at the same time orsimultaneously, that is, when administered sequentially, preferably theadministration of a 4-aryl-piperidine derivative and additional activeingredient occurs less than about one hour apart, more preferably lessthan about 30 minutes apart, even more preferably less than about 15minutes apart, and still more preferably less than about 5 minutesapart.

Preferably, administration of the combination products of the inventionis oral or intravenously, although other routes of administration, asdescribed above, are contemplated to be within the scope of the presentinvention. Although it is preferable that the 4-aryl-piperidinederivative and the additional active ingredients are all administered inthe same fashion (that is, for example, both orally), if desired, theymay each be administered in different fashions (that is, for example,one component of the combination product may be administered orally, andanother component may be administered intravenously). The dosage of thecombination products of the invention may vary depending upon variousfactors such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration, the age, health andweight of the recipient, the nature and extent of the symptoms, the kindof concurrent treatment, the frequency of treatment, and the effectdesired.

Particularly when provided as a single dosage form, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, the preferred dosage forms of the combination products ofthis invention are formulated such that although the active ingredientsare combined in a single dosage form, the physical contact between theactive ingredients is minimized (that is, reduced).

In order to minimize contact, one embodiment of this invention where theproduct is orally administered provides for a combination productwherein one active ingredient is enteric coated. By enteric coating oneor more of the active ingredients, it is possible not only to minimizethe contact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for a combination product wherein one of the active ingredientsis coated with a sustained-release material that effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low-viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-pareils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-pareils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Pharmaceutical kits useful in the methods of the invention are alsowithin the ambit of the present invention. Sterilization of thecontainer may be carried out using conventional sterilizationmethodology well known to those skilled in the art. The sterilecontainers of materials may comprise separate containers, or one or moremulti-part containers, as exemplified by the UNIVIAL™ two-part container(available from Abbott Labs, Chicago, Ill.), as desired. The4-aryl-piperidine derivative and the optional additional activeingredient may be separate, or combined into a single dosage form asdescribed above. Such kits may further include, if desired, one or moreof various conventional pharmaceutical kit components, such as forexample, one or more pharmaceutically acceptable carriers, additionalvials for mixing the components, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

EXAMPLES

The present invention will now be illustrated by reference to thefollowing specific, non-limiting examples. The examples are not intendedto limit the scope of the present invention.

Example 1

Twelve milligrams of alvimopan (two 6 mg capsules) was administeredorally to patients about 120 minutes prior to surgery. The freealvimopan plasma concentration was measured for about 24 hours. Theresults are shown in FIG. 1.

FIG. 1 shows the free plasma concentration of alvimopan (12 mg dose) (innM) as a function of time (in hours). This figure shows that a single 12mg oral dose of alvimopan produced free plasma concentrations sufficientto substantially saturate μ opioid receptors in the GI tract. Maximumconcentrations achieved were 11-fold greater than the Ki. Moreover, theprofile demonstrates that the Ki is exceeded at various times by afactor ranging from approximately 6 to twice the Ki; concentrations thatwould be estimated to produce receptor occupancy of greater than 68%,still within a reasonable interpretation of “substantial saturation.”

Example 2

A randomized, double-blind, placebo-controlled study of different dosesof alvimopan (opioid antagonist) I.V. for 4 days in the presence andabsence of loperamide (opioid) 2 mg p.o. q.i.d. in 60 healthy subjects(n=12 in each of five treatment groups) was carried out. Subjects wererandomly assigned to receive one of the following five treatments:

Group 1: Placebo for alvimopan I.V. b.i.d.+placebo for loperamide p.o.q.i.d. (n=12)Group 2: Placebo for alvimopan I.V. b.i.d.+loperamide 2 mg p.o. q.i.d.(n=12)Group 3: Alvimopan 1 mg I.V. b.i.d.+loperamide 2 mg p.o. q.i.d. (n=12)Group 4: Alvimopan 0.45 mg I.V. b.i.d.+loperamide 2 mg p.o. q.i.d.(n=12)Group 5: Alvimopan 0.1 mg I.V. b.i.d.+loperamide 2 mg p.o. q.i.d. (n=12)Oral SITZMARKS capsules containing radio-opaque markers were beadministered on Days 1, 2, and 3. Alvimopan and loperamide wasadministered at the same time, when applicable.

Study Assessments

Serial blood samples were collected for the determination ofconcentrations of alvimopan and its amide hydrolysis metabolite inplasma.

Subjects were assessed for their pain at the I.V. infusion site using acategorical four-point verbal scale (i.e., no discomfort/pain, milddiscomfort/pain, moderate pain, or severe pain). The Investigator alsoassessed certain characteristics (e.g., erythema) of the I.V. site(i.e., none, mild, moderate, or severe). Abdominal x-rays and x-rays ofstool samples were performed to determine the location of the SITZMARKSmarkers.

The appropriate dose was drawn into the delivery system, normal salinewas added to bring the total volume to 6 mL, and the contents will bemixed thoroughly. Placebo for alvimopan I.V. was 6 mL of normal saline.

Alvimopan or matching placebo and loperamide or matching placebo wereadministered on Days 1 through 4. Note that only the morning doses ofalvimopan and loperamide were administered on Day 4.

Oral SITZMARKS capsules were administered on Days 1, 2, and 3 at thesame time that study medication is administered each day.

Pharmacokinetic Sampling

The first eight subjects in each treatment group followed a fullsampling schedule and the last four subjects followed a sparse samplingschedule. For the first eight subjects (full sampling schedule), bloodsamples was collected just prior to administration of alvimopan I.V. onDays 1 through 4 (four samples); and at 0.5, 1, 1.5, 2, 5, 10, 20, 30,and 60 minutes and at 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120, 144,and 168 hours after the end of the infusion of alvimopan I.V. on Day 4.This is a total of 27 samples per subject (135 mL per subject). For thelast four subjects in each treatment group (sparse sampling schedule),blood was collected prior to administration of alvimopan I.V. on Days 1through 4 (four samples), and immediately following the last infusion onDay 4. Subjects were randomized to have one sample collected during eachof the following intervals, relative to the end of the infusion on Day4:

Interval 1: 3, 5, 10, or 15 minutes

Interval 2: 1, 2, 2.5, or 3 hours

Interval 3: 4, 5, 6, or 8 hours

Interval 4: 10, 12, 14, or 16 hours

Interval 5: 24, 48, 72, or 96 hours

Interval 6: 120 or 144 hours

GI transit score (GITS) was measured by the transit of radio-opaquemarkers administered on Days 1, 2 and 3 with an abdominal x-ray on Day4.

FIG. 2 shows GI score as a function of log of plasma concentrationsmeasured as AUC (τ) (in ng-ml/hr) with a GI score measured byradio-opaque markers in subjects given loperamide with either placebo orone of three doses of I.V. alvimopan (0.1 mg b.i.d, 0.45 mg b.i.d., and1 mg b.i.d.) selected to target different plasma concentrations (4.5,20, and 45 ng/ml, respectively).

The means for the groups are:

AUC (τ) of log AUC (τ) of Alvimopan Alvimopan Group (ng-ml/hr)(ng-ml/hr) GI Score 1 0 — 255.56 2 0 — 208.67 3 4.36 0.639486 231 422.06 1.343606 274.62 5 49.79 1.697142 278.5

The R² value for the means is 0.76. The normal GI score (no loperamide,no alvimopan) was 255.56. Groups 4 and 5 are statistically differentfrom Group 2 and not different from normal (Group 1). This data suggeststhat that plasma concentrations are important in antagonizing the effectof opioids on GI transit. Further, the figures show that increasingexposure, as measured by AUC, which takes into account bothconcentration and time, produces an improved effect (antagonizing theeffect of opioids on GI transit).

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges specific embodiments thereinare intended to be included.

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

What is claimed is:
 1. A method of treating or preventing non-opioidinduced gastrointestinal dysfunction in a patient undergoing surgery,comprising the step of: administering to said patient in need thereofabout 0.5 mg/day to about 18 mg/day of an effective amount of at leastone 4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof; in amanner so as to obtain a pharmacokinetic profile wherein the freeconcentration in the plasma of said patient of said 4-aryl-piperidinederivative or stereoisomer, prodrug, pharmaceutically acceptable salt,hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystallineform thereof is sufficient to achieve substantially saturate the μopioid receptors in the gastrointestinal tract of said patient; whereinsaid patient is not receiving chronic or periodic exogenous opioids;wherein said gastrointestinal dysfunction is postoperative ileus; andwherein said 4-aryl-piperidine derivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.
 2. A method of treating or preventing gastrointestinal dysfunctionin a patient undergoing surgery, comprising the step of: administeringto said patient an effective amount of at least one 4-aryl-piperidinederivative or a stereoisomer, a prodrug, a pharmaceutically acceptablesalt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or anisomorphic crystalline form thereof; in a manner so as to obtain apharmacokinetic profile wherein the plasma or whole blood concentrationof 4-aryl-piperidine of said 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof reaches a maximum concentration from about 30 minutes to about120 minutes prior to said surgery; wherein said gastrointestinaldysfunction is postoperative ileus; and wherein said 4-aryl-piperidinederivative is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid.
 3. A method of treating or preventing gastrointestinal dysfunctionin a patient undergoing surgery, comprising the step of: administeringto said patient an effective amount of at least one 4-aryl-piperidinederivative or a stereoisomer, a prodrug, a pharmaceutically acceptablesalt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or anisomorphic crystalline form thereof; in a manner so as to obtain apharmacokinetic profile wherein the plasma or whole blood concentrationof 4-aryl-piperidine of said 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof reaches a maximum concentration from about 30 minutes to about120 minutes after said administration; wherein said gastrointestinaldysfunction is postoperative ileus; and wherein said 4-aryl-piperidinederivative is[[24[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]aminolaceticacid.
 4. A method according to claim 1, 2, or 3, further comprising thestep of administering at least one opioid to said patient.
 5. A methodaccording to claim 4, wherein said 4-aryl-piperidine derivative orstereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is administered to said patient from about 30 minutes prior tosurgery to less than about 120 minutes prior to said administration ofsaid opioid.
 6. A method according to claim 1, 2, or 3, wherein said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is administered to said patient fromabout 30 minutes prior to surgery to less than about 120 minutes priorto surgery.
 7. A method according to claim 1, 2, or 3, wherein said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is administered orally.
 8. A methodaccording to claim 1, 2, or 3, wherein said 4-aryl-piperidine derivativeor stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is administered parenterally.
 9. A method according to claim 8,wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug,pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate,N-oxide or isomorphic crystalline form thereof is administeredintravenously.
 10. A method according to claim 1, 2, or 3, wherein said[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid is in hydrate form.
 11. A method according to claim 10, whereinsaid[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid is[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid dihydrate.
 12. A method according to claim 11, wherein saidcompound is a substantially pure stereoisomer.
 13. A method according toclaim 12, wherein said[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid is[[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]aceticacid dihydrate.
 14. A method of treating or preventing gastrointestinaldysfunction in a patient undergoing surgery, comprising the step of:administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof; in amanner so as to obtain a pharmacokinetic profile wherein the freeconcentration in the plasma of said patient of 4-aryl-piperidine of said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is sufficient to substantiallysaturate the μ opioid receptors in the gastrointestinal tract of saidpatient; wherein said gastrointestinal dysfunction is postoperativeileus; and wherein said 4-aryl-piperidine derivative is a compound offormula (IA):

wherein: R¹ is hydrogen or alkyl; R² is hydrogen, alkyl or alkenyl; R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl, heteroaryl, or heteroarylalkyl; R⁴ is hydrogen, alkyl oralkenyl; A is OR⁵ or NR⁶R⁷; R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl,cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substitutedalkyl, aralkyl, heteroaryl, or heteroarylalkyl; R⁶ is hydrogen or alkyl;R⁷ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substitutedalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, heteroarylalkyl, aralkyl, B, or alkylene substituted B or,together with the nitrogen atom to which they are attached, R⁶ and R⁷form a heterocyclic ring; B is

C(═O)W or NR⁸R⁹; R⁸ is hydrogen or alkyl; R⁹ is hydrogen, alkyl,alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,cycloalkenyl-substituted alkyl, aryl, aralkyl, heteroaryl, orheteroarylalkyl, or aralkyl or, together with the nitrogen atom to whichthey are attached, R⁸ and R⁹ form a heterocyclic ring; W is OR¹⁰,NR¹¹R¹², or OE; R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl,cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substitutedalkyl, or aralkyl; R¹¹ is hydrogen or alkyl; R¹² is hydrogen, alkyl,alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl,aralkyl or alkylene substituted C(═O)Y or, together with the nitrogenatom to which they are attached, R¹¹ and R¹² form a heterocyclic ring; Eis

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴; R¹³ is alkyl substitutedalkylene; R¹⁴ is alkyl; D is OR¹⁵ or NR¹⁶R¹⁷; R¹⁵ is hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl;R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, aralkyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl; R¹⁷ ishydrogen or alkyl or, together with the nitrogen atom to which they areattached, R¹⁶ and R¹⁷ form a heterocyclic ring; Y is OR¹⁸ or NR¹⁹R²⁰;R¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl; R¹⁹ is hydrogen or alkyl; R²⁰ ishydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl, or, together with the nitrogen atom towhich they are attached, R¹⁹ and R²⁰ form a heterocyclic ring; R²¹ ishydrogen or alkyl; n is 0 to 4; and p is 0 or
 1. 15. A method oftreating or preventing gastrointestinal dysfunction in a patientundergoing surgery, comprising the step of: administering to saidpatient an effective amount of at least one 4-aryl-piperidine derivativeor a stereoisomer, a prodrug, a pharmaceutically acceptable salt, ahydrate, a solvate, an acid salt hydrate, an N-oxide or an isomorphiccrystalline form thereof; in a manner so as to obtain a pharmacokineticprofile wherein the plasma or whole blood concentration of4-aryl-piperidine of said 4-aryl-piperidine derivative or stereoisomer,prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salthydrate, N-oxide or isomorphic crystalline form thereof reaches amaximum concentration from about 30 minutes to about 120 minutes priorto said surgery; wherein said gastrointestinal dysfunction ispostoperative ileus; and wherein said 4-aryl-piperidine derivative is acompound of formula (IA):

wherein: R¹ is hydrogen or alkyl; R² is hydrogen, alkyl or alkenyl; R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl; R⁴ is hydrogen, alkyl or alkenyl; A isOR⁵ or NR⁶R⁷; R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl; R⁶ is hydrogen or alkyl; R⁷ is hydrogen,alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl,cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,heteroarylalkyl, B, or alkylene substituted B or, together with thenitrogen atom to which they are attached, R⁶ and R⁷ form a heterocyclicring; B is

C(═O)W or NR⁸R⁹; R⁸ is hydrogen or alkyl; R⁹ is hydrogen, alkyl,alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,cycloalkenyl-substituted alkyl, aryl, aralkyl, heteroaryl, orheteroarylalkyl or, together with the nitrogen atom to which they areattached, R⁸ and R⁹ form a heterocyclic ring; W is OR¹⁰, NR¹¹R¹², or OE;R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl; R¹¹ is hydrogen or alkyl; R¹² is hydrogen, alkyl, alkenyl,aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, oralkylene substituted C(═O)Y or, together with the nitrogen atom to whichthey are attached, R¹¹ and R¹² form a heterocyclic ring; E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴; R¹³ is alkyl substitutedalkylene; R¹⁴ is alkyl; D is OR¹⁵ or NR¹⁶R¹⁷; R¹⁵ is hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl;R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl; R¹⁷ is hydrogen or alkyl or, togetherwith the nitrogen atom to which they are attached, R¹⁶ and R¹⁷ form aheterocyclic ring; Y is OR¹⁸ or NR¹⁹R²⁰; R¹⁸ is hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl;R¹⁹ is hydrogen or alkyl; R²⁰ is hydrogen, alkyl, alkenyl, aryl,cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkylor, together with the nitrogen atom to which they are attached, R¹⁹ andR²⁰ form a heterocyclic ring; R²¹ is hydrogen or alkyl; n is 0 to 4; andp is 0 or
 1. 16. A method of treating or preventing gastrointestinaldysfunction in a patient undergoing surgery, comprising the step of:administering to said patient an effective amount of at least one4-aryl-piperidine derivative or a stereoisomer, a prodrug, apharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form thereof; in amanner so as to obtain a pharmacokinetic profile wherein the plasma orwhole blood concentration of 4-aryl-piperidine of said 4-aryl-piperidinederivative or stereoisomer, prodrug, pharmaceutically acceptable salt,hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystallineform thereof reaches a maximum concentration from about 30 minutes toabout 120 minutes after said administration; wherein saidgastrointestinal dysfunction is postoperative ileus; and wherein said4-aryl-piperidine derivative is a compound of formula (IA):

wherein: R¹ is hydrogen or alkyl; R² is hydrogen, alkyl or alkenyl; R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl; R⁴ is hydrogen, alkyl or alkenyl; A isOR⁵ or NR⁶R⁷; R⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl,heteroaryl, or heteroarylalkyl; R⁶ is hydrogen or alkyl; R⁷ is hydrogen,alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl,cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,heteroarylalkyl, B, or alkylene substituted B or, together with thenitrogen atom to which they are attached, R⁶ and R⁷ form a heterocyclicring; B is

C(═O)W or NR⁸R⁹; R⁸ is hydrogen or alkyl; R⁹ is hydrogen, alkyl,alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,cycloalkenyl-substituted alkyl, aryl, aralkyl, heteroaryl, orheteroarylalkyl or, together with the nitrogen atom to which they areattached, R⁸ and R⁹ form a heterocyclic ring; W is OR¹⁰, NR¹¹R¹², or OE;R¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, oraralkyl; R¹¹ is hydrogen or alkyl; R¹² is hydrogen, alkyl, alkenyl,aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, oralkylene substituted C(═O)Y or, together with the nitrogen atom to whichthey are attached, R¹¹ and R¹² form a heterocyclic ring; E is

alkylene substituted (C═O)D, or —R¹³OC(═O)R¹⁴; R¹³ is alkyl substitutedalkylene; R¹⁴ is alkyl; D is OR¹⁵ or NR¹⁶R¹⁷; R¹⁵ is hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl;R¹⁶ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkylor cycloalkenyl-substituted alkyl; R¹⁷ is hydrogen or alkyl or, togetherwith the nitrogen atom to which they are attached, R¹⁶ and R¹⁷ form aheterocyclic ring; Y is OR¹⁸ or NR¹⁹R²⁰; R¹⁸ is hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl;R¹⁹ is hydrogen or alkyl; R²⁰ is hydrogen, alkyl, alkenyl, aryl,cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkylor, together with the nitrogen atom to which they are attached, R¹⁹ andR²⁰ form a heterocyclic ring; R²¹ is hydrogen or alkyl; n is 0 to 4; andp is 0 or
 1. 17. A method according to claim 14, 15, or 16, furthercomprising the step of administering at least one opioid to saidpatient.
 18. A method according to claim 17, wherein said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is administered to said patient fromabout 30 minutes to less than about 120 minutes prior to saidadministration of said opioid.
 19. A method according to claim 14, 15,or 16, wherein said 4-aryl-piperidine derivative or stereoisomer,prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salthydrate, N-oxide or isomorphic crystalline form thereof is administeredto said patient from about 30 minutes to less than about 120 minutesprior to surgery.
 20. A method according to claim 14, 15, or 16, whereinsaid 4-aryl-piperidine derivative or stereoisomer, prodrug,pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate,N-oxide or isomorphic crystalline form thereof is administered orally.21. A method according to claim 14, 15, or 16, wherein said4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof is administered parenterally.
 22. Amethod according to claim 21, wherein said 4-aryl-piperidine derivativeor stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof is administered intravenously.
 23. A method according to claim14, 15, or 16, wherein the compound of formula (IA) is a trans3,4-isomer.
 24. A method according to claim 14, 15, or 16, wherein: R¹is hydrogen; R² is alkyl; n is 1 or 2; R³ is benzyl, phenyl, cyclohexyl,or cyclohexylmethyl; and R⁴ is alkyl.
 25. A method according to claim14, 15, or 16, wherein: A is OR⁵; and R⁵ is hydrogen or alkyl.
 26. Amethod according to claim 14, 15, or 16, wherein: A is NR⁶R⁷; R⁶ ishydrogen; R⁷ is alkylene substituted B; and B is C(O)W.
 27. A methodaccording to claim 14, 15, or 16, wherein: R⁷ is (CH₂)_(q)—B; q is about1 to about 3; W is OR¹⁰; and R¹⁰ is hydrogen, alkyl, phenyl-substitutedalkyl, cycloalkyl or cycloalkyl-substituted alkyl.
 28. A methodaccording to claim 14, 15, or 16, wherein: W is NR¹¹R¹² R¹¹ is hydrogenor alkyl; and R¹² is hydrogen, alkyl or alkylene substituted C(═O)Y. 29.A method according to claim 14, 15, or 16, wherein: R¹² is(CH₂)_(m)C(O)Y; m is 1 to 3; Y is OR¹⁸ or NR¹⁹R²⁰; and R¹⁸, R¹⁹ and R²⁰are independently hydrogen or alkyl.
 30. A method according to claim 14,15, or 16, wherein: W is OE; E is CH₂C(═O)D; D is OR¹⁵ or NR¹⁶R¹⁷; R¹⁵is hydrogen or alkyl; R¹⁶ is methyl or benzyl; and R¹⁷ is hydrogen. 31.A method according to claim 14, 15, or 16, wherein: W is OE; E isR¹³OC(═O)R¹⁴; R¹³ is —CH(CH₃)— or —CH(CH₂CH₃)—; and R¹⁴ is alkyl.
 32. Amethod according to claim 14, 15, or 16, wherein p is
 1. 33. A methodaccording to claim 14, 15, or 16, wherein the configuration at positions3 and 4 of the piperidine ring is each R.
 34. A method according toclaim 14, 15, or 16, wherein said compound is selected from the groupconsisting of: Q-CH₂CH(CH₂(C₆H₅))C(O)OH,Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)OCH₂CH₃, Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)OH,Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)NHCH₃,Q-CH₂CH₂CH(C₆H₅)C(O)NHCH₂C(O)NHCH₂CH₃, G-NH(CH₂)₂C(O)NH₂,G-NH(CH₂)₂C(O)NHCH₃, G-NHCH₂C(O)NH₂, G-NHCH₂C(O)NHCH₃,G-NHCH₂C(O)NHCH₂CH₃, G-NH(CH₂)₃C(O)OCH₂CH₃, G-NH(CH₂)₃C(O)NHCH₃,G-NH(CH₂)₂C(O)OH, G-NH(CH₂)₃C(O)OH, Q-CH₂CH(CH₂(C₆H₁₁))C(O)NHCH₂C(O)OH,Q-CH₂CH(CH₂(C₆H₁₁))C(O)NH(CH₂)₂C(O)OH,Q-CH₂CH(CH₂(C₆H₁₁))C(O)NH(CH₂)₂C(O)NH₂, Z—NHCH₂C(O)OCH₂CH₃,Z—NHCH₂C(O)OH, Z—NHCH₂C(O)NH₂, Z—NHCH₂C(O)N(CH₃)₂,Z—NHCH₂C(O)NHCH(CH₃)₂, Z—NHCH₂C(O)OCH₂CH(CH₃)₂,Z—NH(CH₂)₂C(O)OCH₂(C₆H₅), Z—NH(CH₂)C(O)OH, Z—NH(CH₂)₂C(O)NHCH₂CH₃,Z—NH(CH₂)₃C(O)NHCH₃, Z—NHCH₂C(O)NHCH₂C(O)OH, Z—NHCH₂C(O)OCH₂C(O)OCH₃,Z—NHCH₂C(O)O(CH₂)₄CH₃, Z—NHCH₂C(O)OCH₂C(O)NHCH₃,Z—NHCH₂C(O)O-(4-methoxycyclohexyl), Z—NHCH₂C(O)OCH₂C(O)NHCH₂(C₆H₅) andZ—NHCH₂C(O)OCH(CH₃)OC(O)CH₃; wherein: Q represents

G represents

and Z represents


35. A method according to claim 34, wherein said compound is selectedfrom the group consisting of: (+)-Z—NHCH₂C(O)OH, (−)-Z—NHCH₂C(O)OH,(3R,4R)—Z—NHCH₂C(O)NHCH₂(C₆H₅) and (3R,4R)-G-NH(CH₂)₃C(O)OH.
 36. Amethod according to claim 35, wherein said compound is selected from thegroup consisting of: (+)-Z—NHCH₂C(O)OH, and (−)-Z—NHCH₂C(O)OH.
 37. Amethod according to claim 36, wherein said compound is selected from thegroup consisting of: (+)-Z—NHCH₂C(O)OH.
 38. A method according to claim35, wherein said compound is Q-CH₂CH(CH₂(C₆H₅))C(O)OH.
 39. A methodaccording to claim 38, wherein said compound is (3R,4R,S)-Q-CH₂CH(CH₂(C₆H₅))C(O)OH.
 40. A method according to claim 14, 15, or16, wherein said compound is a substantially pure stereoisomer.